A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19

Abstract

Molnupiravir (MK‐4482) is an oral prodrug of the antiviral ribonucleoside analog, N ‐hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well‐tolerated. NHC appeared rapidly in plasma and reached maximum concentration ( C max ), with a median time to C max ( T max ) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC 0–inf ), area under the concentration versus time curve from zero to 12 h (AUC 0–12 ), and C max of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC 0–12 and C max were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC‐TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC‐TP AUC 0–12 and C max were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC C max with comparable AUC 0–inf was seen, supporting administration without regard to food.

Effects of the 5′‐Triphosphate Metabolites of Ribavirin, Sofosbuvir, Vidarabine, and Molnupiravir on CTP Synthase Catalysis and Filament Formation: Implications for Repurposing Antiviral Agents against SARS‐CoV‐2

“…considering that the concentration of N 4 -OHÀ CTP in peripheral blood mononuclear cells has been shown to reach concentrations of 60-85 μM in patients receiving a single oral dose of 1600 mg, [61] i. e., ~20-fold lower than the IC 50 values reported in Table 2.…”

Assessment of pharmacokinetics, safety, and tolerability following twice‐daily administration of molnupiravir for 10 days in healthy participants

“…17 The oral route of administration of molnupiravir makes it convenient for administration to outpatients compared with COVID-19 therapies that require intravenous administration (e.g., remdesivir). Additionally, because molnupiravir has no known drugdrug interactions (DDIs) and can be co-administered without need for dose adjustments, 24 it is an important treatment option for high-risk patients for whom other treatments may not be clinically appropriate due to potential DDIs with medications used to treat common underlying medical Administration of 800 mg molnupiravir q12h for up to 5 days was previously found to be generally well-tolerated in healthy participants and patients with COVID-19; 17,[20][21][22][23] however, a safety and PK evaluation of molnupiravir administered for more than 5 days has not previously been published.…”

“…The PKs of molnupiravir administered for 10.5 days was assessed by evaluating NHC in plasma and NHC-TP in PBMCs, and findings were generally consistent with previously reported studies assessing 5.5 days of molnupiravir administration in healthy Japanese and White participants. 20,23 In this study, plasma NHC T max was ~1.5 h, corresponding to previous studies in both healthy participants and patients with COVID-19 reporting a median T max between 1 and 2 h. [20][21][22][23] As described in previous phase I PK studies, 20,23 concentrations of NHC declined in a biphasic manner, where a rapid distributional phase followed T A B L E 1 Summary statistics of plasma NHC pharmacokinetics following administration of multiple oral doses of molnupiravir 400, 600, and 800 mg every 12 h for 10.5 days in healthy participants.…”

“…NHC is eliminated primarily by metabolism through pathways involved in the metabolism of endogenous pyrimidines. 20,23,24 against coronaviruses and other RNA viruses and a high barrier to the development of resistance. Molnupiravir administration at 800 mg twice daily for 5.5 days is generally well-tolerated and has been shown to reduce the risk of hospitalization or death in nonhospitalized, unvaccinated adults with mild to moderate coronavirus disease 2019 at risk of progression to severe disease.…”

Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants

“…Early therapy lowers the risk of hospitalization or mortality for COVID-19 individuals who are exposed to the prodrug molnupiravir, which has antiviral action. According to Nakamura et al, this was usually well-tolerated after being administered in single and repeated doses [ 101 ]. The drug was permitted to be utilized in Japan under the “special approval for urgency” system based on trial outcomes, as well as universal phase II and phase III data.…”